Methods for producing norgalanthamine, as well as isomers, salts and hydrates thereof

ABSTRACT

The invention relates to processes, which can be performed on an industrial scale, for the production of norgalanthamine, norgalanthamine derivatives and isomers thereof of general formula (A) as well as salts or hydrates thereof with general formula (B). As processes for the production of compounds with general formula (A) or (B), an oxidative demethylation and a catalytic demethylation of the corresponding galanthamine compounds are indicated.

The invention relates to a process for the production ofnorgalanthamine, norgalanthamine derivatives[=(4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,10-de(s)methylgalanthamine, N-demethylgalanthamine, N-norgalanthamine]and isomers thereof with general formula A

as well as salts and hydrates thereof with general formula B

The compounds, which fall under general formula (A) or (B), are keyintermediate products for the production of synthetic galanthaminederivatives, which are used for, i.a., treatment of diseases of thecentral nervous system (CNS), such as Alzheimer's disease.

Compounds of general formulas (A) and (B) are known and can be obtainedfrom, for example, natural substances, see:

Sener, Bilge; Konukol, Sakine; Kruk, Cornelis; Pandit, Upendra K.Alkaloids from Amaryllidaceae. III. Alkaloids from the Bulbs ofPancratium Maritimum. Nat. Prod. Sci. 1998, 4, 148-152

Eichhorn, Jorg; Takada, Takeshi; Kita, Yasuyuki; Zenk, Meinhart H.Biosynthesis of the Amaryllidaceae Alkaloid Galanthamine. Phytochemistry1998, 49, 1037-1047

Almanza, Giovanna R.; Fernandez, Juan M.; Wakori, Edith W. T.;Viladomat, Francesc; Codina, Carles; Bastida, Journe. Alkaloids fromNarcissus cv. Salome. Phytochemistry 1996, 43, 1375-1378

Latvala, Anita; Oenuer, Mustafa A.; Goezler, Tekant; Linden, Anthony;Kivcak, Bijen; Hesse, Manfred. Alkaloids of Galanthus elwesii.Phytochemistry 1995, 39, 1229-1240.

Kreh, Mirko; Matusch, Rudolf. O-Methyloduline and N-Demethylmasonine,Alkaloids from Narcissus Pseudonarcissus. Phytochemistry 1995, 38,1533-1535

Bastida, Jaume; Viladomat, Francesc; Bergonon, Salvador; Fernandez, JuanMarcos; Codina, Carles; Rubiralta, Marlo; Quirion, Jean Charles.Narcissus Alkaloids. Part 19. Alkaloids from Narcissus leonensis.Phytochemistry 1993, 34, 1656-1658

Weniger, B.; Italiano, L.; Beck, J.-P.; Bastida, J.; Bergonon, S.;Codina, C.; Lobstein, A.; Anton, R. Cytotoxic Activity of AmaryllidaceaeAlkaloids. Planta Med. 1995, 61, 77-79

Bastida, J.; Viladomat, F.; Llabres, J. M.; Quiroga, S.; Codina, C.;Rubiralta, M. Narcissus Alkaloids. Part IX. Narcissus Nivalis: A NewSource of Galanthamine. Planta Med. 1990, 56, 123-124

Kihara, Masaru; Kolke, Tomomi; Imakura, Yasuhiro; Kida, Kiyoshi; Shingu,Tetsuro; Kobayashi, Shig-atu. Alkaloidal Constituents of HymenocallisRotata Herb. (Amaryllidaceae). Chem. Pharm. Bull. 1987, 35, 1070-1075

Kobayashi, Shigeru; Ishikawa, Hideki; Kihara, Masaru; Shing, Tetsuro;Uyeo, Shojiro. Isolation of N-Demethylgalanthamine from the Bulbs ofCrinum Asiaticum L. Var. Japanicum Baker (Amaryllidaceae). Chem. Pharm.Bull. 1976, 24, 2553-25555

In addition, it is known to produce compounds of general formula A or Bsynthetically by demethylation of galanthamine.

A two-stage demethylation of galanthamine by degradation of N-oxide isthus described in WO-A1-9703987.

In addition, a two-stage demethylation of galanthamine by reaction withcarboxylic acid derivatives is described in Tetrahedron Lett. 1997, 38,5151, Mary, Aude; Renko, Dolor Zafiarisoa; Guillou, Catherine; Thal,Claude “Selective N-Demethylation of Galanthamine to Norgalanthamine Viaa Non-Classical Polonovski Reaction.”

The two-stage demethylation of galanthamine by reaction withazodicarboxylic acid esters and subsequent saponification is known apriori from U.S. Pat. No. 5,958,903.

In addition, the N-demethylation represents a standard reaction ofalkaloid chemistry, whereby in particular N-dealkylations with thefollowing reagents are known:

-   -   BrCN/Zn

Seiler, Max. P.; Hagenbach, Alexander; Wuethrich, Hans-Juerg; Markstein,Rudolf. J. Med. Chem. 1991, 34, 303-307

-   -   Chloroethyl chloroformate

Ghosh, Debasis; Snyder, Scott E.; Watta, Val J.; Mailman, Richard B.;Nichols, David E. J. Med. Chem. 1996, 39, 549-555

-   -   NaOCl, phase transfer catalysis, then NaOH

Robson, Claire; Meek, Michelle A.; Grunwaldt, Jan-Dierk; Lambert, PeterA.; Queener, Sherry F. J. Med. Chem. 1997, 40, 3040-3048

-   -   N-Iodosuccinimide

Stenmark, Heather G.; Brazzale, Antony; Ma, Zhenkun, J. Org. Chem. 2000,65, 3875-3876

-   -   Methyl chloroformate

Kim, J. C. Org. Prep. Proced. Int. 1977, 9. 1

-   -   Palladium on activated carbon/O₂

Chaudhuri, Naba K.; Servando, Ofella; Markus, Bohdan; Galynker, Igor;Sung, Ming-Sang. J. Indian Chem. Soc. 1985, 62, 899-903

-   -   Ethyl chloroformate

Humber, L. G.; Charest, M. P.; Herr, F. J. Med. Chem. 1971, 14, 982

-   -   Pyridine hydrochloride

Radl, Stanislav, Pyridine Hydrochloride in Organic Synthesis. JanssenChim. Acta 1989, 7, 12-17

-   -   Numerous chloroformates

Olafson, R. A.; Martz, Jonathan T.; Senet, Jean Pierre; Piteau, Marc;Malfroot, Thierry. A New Reagent for the Selective, High-YieldN-Dealkylation of Tertiary Amines: Improved Syntheses of Naltrexone andNalbuphine. J. Org. Chem. 1984, 49, 2081-2082

-   -   BrCN/hydrolysis

Lee, Shoel Sheng; Liu, Yi Chu; Chang, Shu Hwei; Chen, Chung Hsiung.N-Demethylation Studies of Pavine Alkaloids. Heterocycles 1993, 36,1971-1974

-   -   Fe/Fe²⁺/O₂

Sparfel, Daniel; Baranne-Lafont, Joele: Nguyen Kim Cuong; Capdevielle,Patrice; Maurny, Michel. II. Catalytic Oxidation of2-(Aminomethyl)phenols with the System Ferrous Chloride-Iron-Oxygen.Tetrahedron 1990, 46, 803-814

These known processes have the drawback that they can be quite difficultto do on an industrial scale because of their low yields, the relativelyexpensive starting products as well as because of the reactionconditions that are occasionally hazardous.

The object of this invention is therefore to provide a process for theproduction of norgalanthamine, norgalanthamine derivatives as well asisomers thereof, which can also be implemented economically on anindustrial scale. At the same time, however, the end products of theprocess are also to be produced with high purity.

The invention relates to the production of norgalanthamine,norgalanthamine derivatives and isomers thereof with general formula A

as well as salts and hydrates thereof with general formula B

by demethylation of the corresponding galanthamine compounds withgeneral formula (I)

An advantageous process variant according to the invention can beexplained based on the synthesis diagram below:

In this case, the respective galanthamine compounds with general formula(I) are reacted by oxidation in the intermediate product with generalformula (2), the so-called N-oxide intermediate product.

As oxidizing agents, for example, hydrogen peroxide or substitutedperbenozic acids are suitable. M-Chloroperoxybenzoic acid (mCPBA) isespecially preferred.

Then, the norgalanthamine salt that can be easily separated is producedaccording to general formula (B) for example as chloride, oxalate orsulfate, and is separated from the reaction mixture by precipitation.The separated salt already has a high HPLC purity but can be purified inaddition by further recrystallization. As a whole, the process is alsosuitable for implementation on an industrial scale, since a purificationstep using salt precipitation represents a relatively small expense evenon a large scale.

Advantageous process variants according to the invention are explainedin more detail based on the following exemplary embodiments:

EXAMPLE 1 Production of Norgalanthamine Hydrochloride (B, X═HCl)

2.10 kg (7.3 mol) of (−)-galanthamine is dissolved in 12.6 1 ofchloroform while being stirred. In this solution, 1.93 kg (8.5 mol) ofm-chloroperoxybenzoic acid (mCPBA) (75.6%) is added in portions during aperiod of 30-120 minutes such that the temperature of the solution isbetween 15° C. and 50° C. After one to two hours of stirring withouttemperature adjustment, the reaction mixture is cooled to 0-10° C. Asolution of 0.20 kg (0.73 mol) of iron(II) sulfate heptahydrate in 7.30l of water is now added in drops during a period of 40-50 minutes, suchthat the temperature of the reaction mixture remains between 0° C. and10° C. After the addition is completed, the reaction mixture is allowedto stir for 10 more minutes at 0-10° C. After 1.05 kg of concentratedhydrochloric acid is added, 10.0 l of chloroform is then distilled offin a vacuum. The reaction mixture is extracted three times with 9.40 leach of MTBE at 30° C. to 40° C. to remove the benzoic acid. The aqueousphase is stirred for 5 hours to 24 hours at 0° C. to 10° C. Theprecipitate that is produced is suctioned off, washed with 2.0 l of MTBEand dried at 50° C. in a vacuum.

Yield: 1.87 kg (80.5% of theory)

HPLC purity 95.4%

Melting point 173-180° C.: ¹H NMR (DMSO-d₆): δ 9.70 (b, 1.5 H),6.92-6.79 (m, 2H), 6.15 (d, 1H), 5.87 (m, 1H), 4.50 (m, 1H), 4.48-4.03(m, 5H), 3.75 (s, 3H), 2.50-1.80 (m, 5H); ¹³C NMR (DMSO-d₆): δ 147.36 s,145.37 s, 133.67 s, 130.30 d, 126.55 d, 123.33 s, 122.76 d, 112.69 d,87.24 d, 60.33 d, 56.54 q, 49.97 t, 48.03 s, 45.14 t, 35.08 t, 31.63 t.

EXAMPLE 2 Production of Norgalanthamine Oxalate (B, X=Oxalic Acid)

If oxalic acid-dihydrate is used instead of HCl, as in Example 1, theoxalate salt of the norgalanathamine that is formed can be isolated.

Yield: 75% of theory

HPLC purity 96%

Melting point 233-235° C.; ¹H NMR (DMSO-d₆): 6 6.85-6.75 (m, 2H), 6.11(d, J=10.31 Hz, 1H), 5.86 (dd, J=10.31, 4.4 Hz, 1H), 4.54 (b, 1H), 4.47(d, J=15.7 Hz, 1H), 4.24 (d, J=15.1 Hz, 1H), 4.09 (b, 1H), 3.79 (s, 3H),3.55-3.40 (m, 2H), 2.54-2.46 (m, 1H), 2.35-2.20 (m, 1H), 2.16-1.82 (m,3H); ¹³C NMR (DMSO-d₆): δ 164.9 (s), 146.5 (s,), 144.5 (s), 132.9 (s),129.5 (d), 125.7 (d), 122.8 (s), 121.7 (d), 111.7 (d), 86.4 (d), 59.6(d), 55.7 (q), 49.4 (t), 47.2 (s), 44.4 (t), 34.4 (t), 30.8 (t); Anal.cld. for C₁₆H₁₉NO₃.C₂H₂O₄.0.5 H₂O: C, 58.06; H, 5.95; N, 3.76. Fnd: C,57.91; H, 5.88; N, 3.69.

EXAMPLE 3 Purification of Norgalanthamine-Hydrochloride (B, X=HCl)

5.20 kg (16.8 mol) of (−)-norgalanthamine-HCl is taken up as a crudeproduct in 10.4 l of water and dissolved at reflux temperature whilebeing stirred. After 10-15 minutes of stirring at reflux temperature, itwas cooled to 0-10° C. and stirred for 1 to 24 hours at thistemperature. The precipitate is suctioned off and washed with 1.0 l ofwater and dried at 50° C. for 80-120 hours in a vacuum.

Yield: 3.96 kg (76.2% of theory)

HPLC purity 98.9%

Below, a comparison is made with the closest prior art, which is theteaching according to WO-A1-9703987.

1) Production of N-Oxide Intermediate Compound (2):

In WO-A1-9703987, the N-oxide formation is mentioned as a standardprocess. Without detailed information, it should be assumed that thisintermediate product is produced and then—as depicted below—is subjectedto an expensive purification.

2) Production of Compound B by Means of FeSO₄ Reduction from (2):Parameters WO-A1-9703987 Sanochemia Process Batch Size 1.73 g 2.1 kgAmount of Approximately 60x Approximately 10x Solvent Eq. Iron 2 0.1Sulfate Heptahydrate Working-up Evaporation to the Dry Mixing with HCl,State, Extraction Between Concentration by Methylene Chloride andEvaporation to 50% and NaHCO₃ Solution Extraction Between Water and MTBEIsolation of As a Free Base by HCl Salt by Cooling, and the ProductConcentration by Suctioning-off of the Evaporation to the Dry AqueousPhase State Purification Column Chromatography Recrystallization EndProduct Free Base HCl Salt or Oxalate Salt

Advantages of the process according to the invention compared to theprocess from WO-A1-9703987:

The reaction volume is significantly less by using ⅙ of the amount ofsolvent in comparison to WO-A1-9703987.

By using only 5% iron sulfate heptahydrate, the reaction mixturecontains considerably lower iron residues than those associated withWO-A1-9703987.

During working-up, the reaction mixture is concentrated by evaporationto 50% of the total volume. Concentration by evaporation to the drystate, as is done even twice in WO-A1-9703987, is quite difficult to doon an industrial scale.

The end product of the process with general formula (B) is precipitatedfrom the aqueous reaction mixture, for example, as a crystallinehydrochloride salt by cooling; conversely, a “white foam” that can bequite difficult to process further is formed according to WO-A-19703987.

A purification of the end product of the process according to generalformula (B) to a degree of purity of >98% is possible by simplerecrystallization from water. An expensive purification of the processproduct by column chromatography is not necessary, however, in contrastto WO-A1-9703987.

In summary, it can be said that this process variant according to theinvention, because of the low iron residues and the reduced amount ofsolvent, is especially suitable for implementation on an industrialscale, whereby at the same time, however, satisfactory degrees of purityare achieved.

In addition, the invention relates to a process for the production ofnorgalanthamine, norgalanthamine derivatives as well as isomers thereofwith general formula B from the corresponding galanthamine compounds (1)by means of catalytic demethylation. In this case, the reaction mixturecontains suitable solvents or solvent mixtures, which in any casecontain methanol. As catalysts, transition metals, preferably palladium,are treated on a suitable support material, preferably calciumcarbonate, with an oxygen-containing gas mixture, preferably air, whichis saturated in solvent mixtures. In addition, in an especiallyadvantageous way, a gas mixture that consists of oxygen in a proportionof 3 to 30% by volume and an inert gas such as nitrogen or argon can beused. Then, the catalyst is separated from the reaction mixture, and theend product of the process with general formula B is obtained incrystalline form, e.g., as an oxalate or hydrochloride salt. Thisprocess variant according to the invention has the advantage that incontrast to the known processes, the reaction sequence is accomplishedin one stage, and no hazardous or toxic reagents have to be used.

This process variant according to the invention is explained in moredetail based on the following reaction diagram as well as an embodiment:

EXAMPLE 4 Production of(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-6H-benzofuro[3a,3,2-ef][2]-benzazepin-6-ol,Norgalanthamine Hydrochloride (B)

10 g of galanthamine, free base, and 8 g of palladium on calciumcarbonate (10%, Fluka) are introduced into an open 2 l—three-neckedflask, 1 l of methanol, distilled over potassium carbonate, is added,the mixture is stirred with a magnetic stirrer and heated with an oilbath to 50° C. After seven hours of stirring, the reaction mixture iscooled, and the catalyst is allowed to settle. The solution from whichcatalyst is removed by decanting is concentrated by evaporation to thedry state in a Rotavapor at a bath temperature of 50° C., the residue isdissolved in 100 ml of 2N hydrochloric acid, made basic with 30% sodiumhydroxide solution, and shaken out 3× with 30 ml each of chloroform. Thecombined organic phases are concentrated by evaporation to the dry statein a Rotavapor at a bath temperature of 50° C. The residue is taken upin 300 ml of ethyl acetate, acidified with 10% ethereal hydrochloricacid, and the precipitate is filtered off. After washing is continuedonce more with 20 ml of ethyl acetate, the norgalanthamine hydrochloride(B, X═HCl) is dried at 60° C. and 25 mbar.

Yield 9.4 g (95% of theory)

HPLC Purity 87.3%

Melting point 166-171° C.:

EXAMPLE 5 Production of(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-6H-benzofuro-3a,3,2-ef][2]-benzazepin-6-ol,Norgalanthamine (A)

Release of norgalanthamine A from the oxalate salt or from thehydrochloride salt:

The norgalanthamine salt (oxalate B, X═HCl or hydrochloride B, X=oxalicacid) was dispersed between CH₂Cl₂ and concentrated NH₄OH solution, andthe aqueous phase was exhaustively extracted with CH₂Cl₂. The combinedorganic phases were dried (Na₂SO₄), filtered, and solvent was removed ina rotary evaporator, by which A was obtained with yields of between 95%and 99% in the form of colorless crystals.

Melting point 145-146° C.; TLC; CHCl₃; MeOH: concentrated NH₄OHsolution=90; 8.5: 1.5; ¹H NMR (CDCl₃): δ 6.65-6.52 (m, 2H), 6.06-5.92(m, 2H), 4.57 (b, 1H) 4.15-4.08 (m, 1H), 3.95 (d, J5.7 Hz, 2H), 3.79 (s,3H), 3.34 (ddd, J=14.6, J=3.5 Hz, J=3.5 Hz, 1H), 3.18 (ddd, J=13.2,J=11.4, J=2.6 Hz, 1H), 2.66 (ddd, J=15.7, J=1.63, J=1.63 Hz, 1H), 2.27(b, 2H), 1.98 (ddd, J=15.7, J=5.0, J=2.4 Hz, 1H), 1.88-1.61 (m, 2H); ¹³CNMR (CDCl₃): δ 146.2 (s), 143.9 (s), 133.1 (s), 133.0 (s), 127.6 (d127.0 (d), 120.5 (d), 111.0 (d), 88.5 (d), 61.9 (d), 55.8 (q), 53.8 (t),48.7 (s), 47.0 (t), 40.3 (t), 29.9 (t); Anal. cld. for C₁₆H₁₉NO₃: C,70.31; H, 7.01; N, 5.12. Fnd: C, 70.05; H, 7.01: N, 4.97.

In summary, it can be said that possible methods of production that canbe implemented on an industrial scale with the process according to theinvention for the production of norgalanthamine, norgalanthaminederivatives and isomers thereof, as well as salts and hydrates thereof,by N-demethylation from the corresponding galanthamine compounds areindicated. In this case, in a variant according to the invention, thecorresponding galanthamine compound (1) is reacted by oxidativedemethylation in an N-oxide intermediate product of general formula (2).This intermediate product with general formula (2) is then convertedinto salts or hydrates of norgalanthamines, norgalanthamine derivativesas well as isomers thereof with general formula (B) or into the freebases with general formula (A). Salts, such as chlorides, oxalates andsulfates, are preferably formed, which can be separated in a simple wayfrom the reaction mixture by precipitation. If necessary, an additionalpurification step is possible in a simple way by recrystallization.

Another variant according to the invention for the production ofnorgalanthamine, norgalanthamine derivatives and isomers thereof as wellas salts and hydrates thereof is indicated according to the invention bya one-stage catalytic methylation from the galanthamine compounds withgeneral formula (B). In this case, the corresponding norgalanthamine,norgalanthamine derivative or isomer thereof is obtained in the form ofits salt or as a free base in a one-stage reaction.

1. Process for the production of norgalanthamine, norgalanthaminederivatives and isomers thereof with general formula (A)

as well as salts and hydrates thereof with general formula (B)

by demethylation of the corresponding galanthamine compounds withgeneral formula (1)


2. Process according to claim 1, characterized in that the demethylationreaction is an oxidative demethylation reaction.
 3. Process according toclaim 2, wherein peroxides are used as oxidizing agents.
 4. Processaccording to claim 3, wherein substituted and/or unsubstitutedperbenzoic acids, in particular m-chloroxybenzoic acid (nCPBA), are usedas peroxides.
 5. Process according to claim 2, wherein an N-oxideintermediate product with general formula (2)

is formed by oxidative demethylation.
 6. Process according to claim 5,wherein the compounds of general formula (A) or (B) are formed from theN-oxide intermediate product with general formula (2).
 7. Processaccording to claim 6, wherein the compounds with general formula (B) areformed in the form of their salts preferably by the addition ofhydrochloric acid and/or oxalic acid.
 8. Process according to claim 6,wherein the compounds with general formula (B) are formed in the form ofsulfates by adding iron sulfate, in particular iron sulfate heptahydratein a 0.1 to 2.0 equimolar amount.
 9. Process according to claim 7,wherein the salts of the compounds with general formula (B) are formedby recrystallization from one or more solvents.
 10. Process according toclaim 1, wherein the demethylation reaction is performed in the presenceof a catalyst.
 11. Process according to claim 10, wherein the reactionthat is performed in the presence of a catalyst is a one-stage reaction.12. Process according to claim 10, wherein palladium is used as acatalyst.
 13. Process according to claim 10, wherein the catalyst isused with a support material, preferably calcium carbonate.
 14. Processaccording to claim 11, wherein the catalytic N-methylation reaction isperformed in a solvent mixture that contains at least methanol. 15.Process according to claim 10, wherein for the demethylation reaction, amixture of oxygen, preferably 3 to 30% oxygen by volume, and an inertgas, preferably nitrogen or argon, is used.
 16. Process according toclaim 8, wherein the salts of the compounds with general formula (B) areformed by recrystallization from one or more solvents.
 17. Processaccording to claim 11, wherein palladium is used as a catalyst. 18.Process according to claim 3, wherein an N-oxide intermediate productwith general formula (2)

is formed by oxidative demethylation.
 19. Process according to claim 4,wherein an N-oxide intermediate product with general formula (2)

is formed by oxidative demethylation.